In recent years, major advances in tumor immunology have led to an increased understanding of the immune responses against tumors. For example, with respect to melanoma, human melanoma and other tumor cells express antigens that are recognized by cytotoxic T lymphocytes (CTL) derived from cancer patients (Boon and van der Bruggen (1996) J Exp Med 183:725-9; Rosenberg (2001) Nature 411:380-4; Renkvist and Parmiani (2001) Cancer Immunol Immunother 50:3-15). The cascade of molecular recognition events associated with these tumor-associated immune responses involve the expression of specific peptides in complex with MHC class I molecules on the cancer cells. For example, human melanomas express tumor-associated peptides that are presented to the immune system in a complex with class I HLA-A2 molecules (Anichini et al. (1993) J. Exp. Med. 177:989-98; Coulie et al. (1994) J. Exp. Med. 180:35-42). Several categories of cancer-associated antigens have been reported as targets for CTLs in vitro and in vivo such as cancer-testis antigens that are expressed in different tumors and in normal testis, melanocyte differentiation antigens, point mutations of normal genes, antigens that are overexpressed in malignant tissues, and viral antigens (Renkvist and Parmiani (2001) Cancer Immunol Immunother 50:3-15). Although there is strong experimental evidence demonstrating the presence of these antigens on a variety of tumors, they are apparently unable to elicit a strong enough anti-tumor immune response (Rivoltini et al. (1998) Crit Rev Immunol 18:55-63).
Therefore many modern cancer immunotherapy approaches are now designed to induce and enhance T cell reactivity against these tumor antigens. Intensive research on cancer peptides has culminated in many clinical trials involving therapeutic vaccination of cancer patients with antigenic peptides or proteins (Rosenberg (2001) Nature 411:380-4; Offringa and Melief (2000) Curr Opin Immunol 12:576-82). Moreover, several studies demonstrated that the inability of the patient's immune system to elicit an effective immune response against the tumor is often due to poor antigen presentation (Restifo et al. (1993) J. Exp. Med. 177:265-72; Seliger and Ferrone (2000) Immunol. Today 21:455-64). Nevertheless, these studies have encouraged the development of new immunotherapeutic strategies that employ vaccination protocols with tumor cells, tumor extracts, RNA-loaded dendritic cells, or tumor cell-dendritic cell hybrid vaccination (Esche (1999) Curr Opin Mol Ther 1:72-81; Kugler et al. (2000) Nat. Med. 6:332-36). Tumor-specific MHC-peptide complexes present on the surface of tumor cells may also offer a unique and specific target for an antibody-based therapeutic approach. To develop such a strategy, targeting moieties such as recombinant antibodies that will specifically recognize peptide-MHC complexes must be isolated.
The recent advent of MHC-peptide tetramers has provided a new tool for studying antigen-specific T cell populations in health and disease, even when they are very rare, by monitoring tetramer-T cell binding via flow cytometry (Altman et al. (1996) Science 274:94-96; Lee et al. (1999) Nat. Med. 5:677-85; Ogg et al. (1998) Science 279:2103-06). However, to date there are very few tools available to detect, visualize, count, and study antigen (MHC-peptide) presentation. Indeed, several studies demonstrated that the inability of the patient's immune system to elicit an effective immune response against the tumor is often due to poor antigen presentation (Restifo et al. (1993) J. Exp. Med. 177:265-72; Seliger and Ferrone (2000) Immunol. Today 21:455-64). Antibodies with T cell receptor-like specificity could enable measuring the antigen presentation capabilities of such tumor or antigen presenting cells, for example by direct visualization of the specific MHC-peptide complex on the cell surface. Some attempts to use recombinant soluble T cell receptors for this purpose have largely failed because of their inherent low affinity for their target as well as their instability as recombinant-engineered molecules (Wulfing and Pluckthun (1994) J Mol Biol 242:655-69). Therefore, in addition to being used as targeting agents, TCR-like antibodies would serve as a valuable tool to obtain precise information about the presence, expression pattern, and distribution of the target tumor antigen, i.e., the MHC-peptide complex, on the tumor cell surface, on tumor metastases, in lymphoid organs, and on professional antigen-presenting cells.
Antibodies that specifically recognize class I MHC-peptide complexes have been used in murine systems to study antigen presentation, to localize and quantify antigen-presenting cells displaying a T cell epitope, or as a targeting tool in a mouse model (Andersen et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93:1820-24; Porgador (1997) Immunity 6:715-26; Day (1997) Proc Natl Acad Sci USA 94:8064-9; Zhong (1997) Proc Natl Acad Sci USA 1997 94, 13856-61; Zhong (1997) J Exp Med. 186, 673-82; Dadaglio (1997) Immunity 6, 727-38; Murphy et al. (1989) Nature 338:765-8; Aharoni (1991) Nature. 351:147-50; Krogsgaard et al. (2000) J Exp Med. 191, 1395-412; Reiter and Pastan (1997) Proc. Natl. Acad. Sci. U.S.A. 94:4631-36).